Adaptive Fat Oxidation Is Coupled with Increased Lipid Storage in Adipose Tissue of Female Mice Fed High Dietary Fat and Sucrose.

Western diets high in fat and sucrose are associated with metabolic syndrome (MetS). Although the prevalence of MetS in women is comparable to that in men, metabolic adaptations in females to Western diet have not been reported in preclinical studies. This study investigates the effects of Western diet on risk factors for MetS in female mice. Based on our earlier studies in male mice, we hypothesized that dietary supplementation with extracts of Artemisia dracunculus L. (PMI5011) and Momordica charantia (bitter melon) could affect MetS risk factors in females. Eight-week-old female mice were fed a 10% kcal fat, 17% kcal sucrose diet (LFD); high-fat, high-sucrose diet (HFS; 45% kcal fat, 30% kcal sucrose); or HFS diet with PMI5011 or bitter melon for three months. Body weight and adiposity in all HFS groups were greater than the LFD. Total cholesterol level was elevated with the HFS diets along with LDL cholesterol, but triglycerides and free fatty acids were unchanged from the LFD. Over the three month period, female mice responded to the HFS diet by adaptive increases in fat oxidation energy in muscle and liver. This was coupled with increased fat storage in white and brown adipose tissue depots. These responses were enhanced with botanical supplementation and confer protection from ectopic lipid accumulation associated with MetS in female mice fed an HFS diet.

Potential adverse effects of botanical supplementation in high-fat-fed female mice.

BACKGROUND: Insulin resistance underlies metabolic syndrome and is associated with excess adiposity and visceral fat accumulation, which is more frequently observed in males than females. However, in young females, the prevalence of metabolic syndrome is rising, mainly driven by accumulation of abdominal visceral fat. The degree to which sex-related differences could influence the development of insulin resistance remains unclear, and studies of potential therapeutic strategies to combat metabolic syndrome using rodent models have focused predominantly on males. We therefore evaluated the effects of two nutritional supplements derived from botanical sources, an extract of Artemisia dracunculus L. (termed PMI5011) and Momordica charantia (commonly known as bitter melon), on female mice challenged with a high-fat diet in order to determine if dietary intake of these supplements could ameliorate obesity-induced insulin resistance and metabolic inflexibility in skeletal muscle. METHODS: Body composition, physical activity and energy expenditure, fatty acid oxidation, insulin signaling, and gene and protein expression of factors controlling lipid metabolism and ectopic lipid accumulation were evaluated in female mice fed a high-fat diet supplemented with either PMI5011 or bitter melon. Statistical significance was assessed by unpaired two-tailed t test and repeated measures ANOVA. RESULTS: PMI5011 supplementation resulted in increased body weight and adiposity, while bitter melon did not induce changes in these parameters. Pyruvate tolerance testing indicated that both supplements increased hepatic glucose production. Both supplements induced a significant suppression in fatty acid oxidation in skeletal muscle homogenates treated with pyruvate, indicating enhanced metabolic flexibility. PMI5011 reduced lipid accumulation in skeletal muscle, while bitter melon induced a downward trend in lipid accumulation in the skeletal muscle and liver. This was accompanied by transcriptional regulation of autophagic genes by bitter melon in the liver. CONCLUSIONS: Data from the current study indicates that dietary supplementation with PMI5011 and bitter melon evokes a divergent, and generally less favorable, set of metabolic responses in female mice compared to effects previously observed in males. Our findings underscore the importance of considering sex-related variations in responses to dietary supplementation aimed at combating metabolic syndrome.

Groundsel Bush (Baccharis halimifolia) Extract Promotes Adipocyte Differentiation In Vitro and Increases Adiponectin Expression in Mature Adipocytes.

An ethanolic extract of Baccharis halimifolia (groundsel bush, GB), which is a native Louisiana plant with documented use in Creole folk medicine, has been shown to inhibit lipopolysaccharide (LPS)-induced inflammation in cultured macrophages. Here, we examine the effects of GB on adipocyte development and function, as these processes are attractive targets for intervention in insulin resistance. Oil Red O neutral lipid staining, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and immunoblotting were used to measure GB effects on lipid accumulation, gene expression, and protein abundance, respectively. In differentiating 3T3-L1 adipocytes, GB enhanced lipid accumulation and increased expression of several adipogenic genes (GLUT4, aP2, ADPN, CEBPα, FAS, and PPARγ). Protein levels of two of these adipogenic markers (aP2 and adiponectin) were examined and found to be induced by GB treatment. In mature adipocytes, GB reduced the gene expression of resistin, a pro-inflammatory endocrine factor, increased the adiponectin protein levels in a time-dependent manner, and substantially attenuated the TNF-alpha-induced reduction in adiponectin. In macrophages, GB reduced the expression of pro-inflammatory genes that were induced by LPS. GB produces metabolically favorable changes in differentiating adipocytes, mature adipocytes, and macrophages in vitro, suggesting its potential use as a dietary supplement or nutraceutical to support metabolic health and resiliency.

Diosgenin, 4-hydroxyisoleucine, and fiber from fenugreek: mechanisms of actions and potential effects on metabolic syndrome.

Metabolic syndrome and its complications continue to rise in prevalence and show no signs of abating in the immediate future. Therefore, the search for effective treatments is a high priority in biomedical research. Products derived from botanicals have a time-honored history of use in the treatment of metabolic diseases including type 2 diabetes. Trigonella foenum-graecum, commonly known as fenugreek, is an annual herbaceous plant that has been a staple of traditional herbal medicine in many cultures. Although fenugreek has been studied in both clinical and basic research settings, questions remain about its efficacy and biologic mechanisms of action. Diosgenin, 4-hydroxyisoleucine, and the fiber component of the plant are the most intensively studied bioactive constituents present in fenugreek. These compounds have been demonstrated to exert beneficial effects on several physiologic markers including glucose tolerance, inflammation, insulin action, liver function, blood lipids, and cardiovascular health. Although insights into the molecular mechanisms underlying the favorable effects of fenugreek have been gained, we still do not have definitive evidence establishing its role as a therapeutic agent in metabolic disease. This review aims to summarize the currently available evidence on the physiologic effects of the 3 best-characterized bioactive compounds of fenugreek, with particular emphasis on biologic mechanisms of action relevant in the context of metabolic syndrome.

St. John's Wort Has Metabolically Favorable Effects on Adipocytes In Vivo.

In addition to serving as a storage site for reserve energy, adipocytes play a critical role in whole-body insulin sensitivity and glucose metabolism. St. John's Wort (SJW) is a botanical supplement widely used as an over-the-counter treatment of depression and a variety of other conditions associated with anxiety and nerve pain. Previous studies in our laboratory demonstrated that SJW inhibits insulin-stimulated glucose uptake and adipocyte differentiation in cultured murine and mature human adipocytes. To investigate the effects of SJW on adipocyte function in vivo, we utilized C57BL/6J mice. In our studies, mice were administered SJW extract (200 mg/kg) once daily by gavage for two weeks. In contrast to our in vitro studies, mice treated with SJW extract showed increased levels of adiponectin in white adipose tissue in a depot specific manner (P < 0.01). SJW also exerted an insulin-sensitizing effect as indicated by a significant increase in insulin-stimulated Akt serine phosphorylation in epididymal white adipose tissue (P < 0.01). Food intake, body weight, fasting blood glucose, and fasting insulin did not differ between the two groups. These results are important as they indicate that SJW does not promote metabolic dysfunction in adipose tissue in vivo.

Artemisia scoparia enhances adipocyte development and endocrine function in vitro and enhances insulin action in vivo.

BACKGROUND: Failure of adipocytes to expand during periods of energy excess can result in undesirable metabolic consequences such as ectopic fat accumulation and insulin resistance. Blinded screening studies have indicated that Artemisia scoparia (SCO) extracts can enhance adipocyte differentiation and lipid accumulation in cultured adipocytes. The present study tested the hypothesis that SCO treatment modulates fat cell development and function in vitro and insulin sensitivity in adipose tissue in vivo. METHODS: In vitro experiments utilized a Gal4-PPARγ ligand binding domain (LBD) fusion protein-luciferase reporter assay to examine PPARγ activation. To investigate the ability of SCO to modulate adipogenesis and mature fat cell function in 3T3-L1 cells, neutral lipid accumulation, gene expression, and protein secretion were measured by Oil Red O staining, qRT-PCR, and immunoblotting, respectively. For the in vivo experiments, diet-induced obese (DIO) C57BL/6J mice were fed a high-fat diet (HFD) or HFD containing 1% w/w SCO for four weeks. Body weight and composition, food intake, and fasting glucose and insulin levels were measured. Phospho-activation and expression of insulin-sensitizing proteins in epididymal adipose tissue (eWAT) were measured by immunoblotting. RESULTS: Ethanolic extracts of A. scoparia significantly activated the PPARγ LBD and enhanced lipid accumulation in differentiating 3T3-L1 cells. SCO increased the transcription of several PPARγ target genes in differentiating 3T3-L1 cells and rescued the negative effects of tumor necrosis factor α on production and secretion of adiponectin and monocyte chemoattractant protein-1 in fully differentiated fat cells. DIO mice treated with SCO had elevated adiponectin levels and increased phosphorylation of AMPKα in eWAT when compared to control mice. In SCO-treated mice, these changes were also associated with decreased fasting insulin and glucose levels. CONCLUSION: SCO has metabolically beneficial effects on adipocytes in vitro and adipose tissue in vivo, highlighting its potential as a metabolically favorable botanical supplement.